Metastin is a C-terminal amide type single chain peptide consisting of 54 amino acid residues, and was found as an endogenous ligand of seven-transmembrane receptor GPR54 coupled with Gq protein. The amino acid sequence of metastin matches with the amino acid sequence of a gene product fragment of human cancer metastasis suppressor gene KiSS-1. In fact, a report has documented that metastin indeed significantly inhibited metastasis of lung transitional GPR54-expressing melanoma (e.g., Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Nature. 2001, 411, 613-7.). Likewise, it has been clarified that metastin also suppresses the mobility of GPR54-expressing pancreatic cancer cells (e.g., Masui T, Doi R, Mori T, Toyoda E, Koizumi M, Kami K, Ito D, Peiper S C, Broach J R, Oishi S, Niida A, Fujii N, Imamura M. Biochem Biophys Res Commun. 2004 Feb. 27; 315(1):85-92.). In addition, since metastin is isolated from human placenta, and its blood concentration is markedly high in the gastation period, and further, since GPR54 is strongly expressed in the pituitary gland and the like, the role of the metastin/GPR54 system in the control of sexual function is drawing attention. In recent years, moreover, it has been reported that the action of an agonist on the intracerebral GPR54 promotes release of sex hormones such as gonadotropin and the like, and the functional deficiency of GPR54 causes the sexual hypofunction. Therefore, the metastin/GPR54 system is a highly attractive drug discovery target for both the suppression of cancer metastasis and sexual functional disease.
The present inventors have initiated a creative investigation of a low molecular agonist with the aim to develop a novel chemotherapeutic agent targeting GPR54. As a first step, the present inventors conducted investigation to lower the molecular weight of metastin using metastin (45-54) (SEQ ID NO: 1) as a base skeleton which shows about 10-fold GPR54 binding affinity as compared to full-length metastin. Based on the information in the literatures, they configured an RW-amide skeleton on the C-terminal side, designed a short chain peptide having a basic functional group on the N-terminal side via a spacer, and performed synthesis, activity evaluation of various derivatives. As a result, they have found 5 residue peptide derivative FM052a1 (molecular weight 992.2: SEQ ID NO: 2) and FM053a2 (molecular weight B52.0: SEQ ID NO: 3), having a GPR54 agonist activity equivalent to that of metastin (molecular weight 5857.5) and drastically low molecular weights (e.g., Horikoshi, Y.; Matsumoto, H.; Takatsu, Y.; Ohtaki, T.; Kitada, C.; Usuki, S.; Fujino, M. J. Clin. Endocrinol. Metab. 2003, 88, 914-919.). The present inventors have tried to develop novel GPR54 agonist having still higher activity.